Highly cooperative opening of calcium channels by inositol 1,4,5-trisphosphate.
The kinetics of calcium release by inositol 1,4,5-trisphosphate (IP3) in permeabilized rat basophilic leukemia cells were studied to obtain insight into the molecular mechanism of action of this intracellular messenger of the phosphoinositide cascade. Calcium release from intracellular storage sites was monitored with fura-2, a fluorescent indicator. The dependence of the rate of calcium release on the concentration of added IP3 in the 4 to 40 nM range showed that channel opening requires the binding of at least three molecules of IP3. Channel opening occurred in the absence of added adenosine triphosphate, indicating that IP3 acts directly on the channel or on a protein that gates it. The channels were opened by IP3 in less than 4 seconds. The highly cooperative opening of calcium channels by nanomolar concentrations of IP3 enables cells to detect and amplify very small changes in the concentration of this messenger in response to hormonal, sensory, and growth control stimuli.


Roles of crustacean hyperglycaemic hormone in ionic and metabolic homeostasis in the Christmas Island blue crab, Discoplax celeste.
There is a growing body of evidence implicating the involvement of crustacean hyperglycaemic hormone (CHH) in ionic homeostasis in decapod crustaceans. However, little is known regarding hormonally influenced osmoregulatory processes in terrestrial decapods. As many terrestrial decapods experience opposing seasonal demands upon ionoregulatory physiologies, we reasoned that these would make interesting models in which to study the effect of CHH upon these phenomena. In particular, those (tropical) species that also undergo seasonal migrations might be especially informative, as we know relatively little regarding the nature of CHHs in terrestrial decapods, and hormonally mediated responses to seasonal changes in metabolic demands might also be superimposed or otherwise integrated with those associated with ionic homeostasis. Using Discoplax celeste as a model crab that experiences seasonal extremes in water availability, and exhibits diurnal and migratory activity patterns, we identified two CHHs in the sinus gland. We biochemically characterised (cDNA cloning) one CHH and functionally characterised (in terms of dose-dependent hyperglycaemic responses and glucose-dependent negative feedback loops) both CHHs. Whole-animal in situ branchial chamber (22)NaCl perfusion experiments showed that injection of both CHHs increased gill Na(+) uptake in a seasonally dependent manner, and (51)Cr-EDTA clearance experiments demonstrated that CHH increased urine production by the antennal gland. Seasonal and salinity-dependent differences in haemolymph CHH titre further implicated CHH in osmoregulatory processes. Intriguingly, CHH appeared to have no effect on gill Na(+)/K(+)-ATPase or V-ATPase activity, suggesting unknown mechanisms of this hormone's action on Na(+) transport across gill epithelia.


PacBio Genome Sequences of Escherichia coli Serotype O157:H7, Diffusely Adherent E. coli, and Salmonella enterica Strains, All Carrying Plasmids with an mcr-1 Resistance Gene.
We report here Illumina-corrected PacBio whole-genome sequences of an Escherichia coli serotype O157:H7 strain (2017C-4109), an E. coli serotype O[undetermined]:H2 strain (2017C-4173W12), and a Salmonella enterica subsp. enterica serovar Enteritidis strain (2017K-0021), all of which carried the mcr-1 resistance gene on an IncI2 or IncX4 plasmid. We also determined that pMCR-1-CTSe is identical to a previously published plasmid, pMCR-1-CT.


The Effect of Everolimus on Scar Formation in Glaucoma Filtering Surgery in a Rabbit Model.
To investigate the efficiency of everolimus on the prevention of postoperative scar in a rabbit model of glaucoma filtering surgery in comparison with mitomycin-C (MMC). Thirty New Zealand albino rabbits were randomly assigned into 3 groups, each including ten rabbits: an everolimus group (Group 1), a MMC group (Group 2), and a sham group (Group 3). A limbal-based trabeculectomy was performed on the right eyes of all the rabbits. For 28 days following surgery, the eyes were evaluated in terms of intraocular pressure (IOP), morphological and biomicroscopic changes, and complications in the bleb. On the 28th day, four eyes randomized from each group were enucleated and histologically and immunohistochemically analyzed. Transforming growth factor-β1 (TGF-β1), metalloproteinase (MMP-2, MMP-9), and proliferative cell nuclear antigen (PCNA) expressions in each group were evaluated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was used for apoptosis. Bleb survival was statistically significantly longer for a period in Group 1 compared to Group 2. When postoperative IOPs of three groups were measured, it was seen that there is significant IOP reduction in all three groups. However, there were increases in the mean IOP values beginning from the 5th day in Group 2 and from the 3rd day in Group 3 while in Group 1 mean IOP values began to increase beginning from 10th day and the mean IOP values in Group 1 remained at a lower level in comparison to the other groups for 28 days (p < 0.05). The expressions of TGF-β1, MMP-2, MMP-9, and PCNA were reduced in Group 1 compared to other groups. TUNEL positive apoptotic cells were significantly increased in Group 1 compared to other groups (p < 0.05). Everolimus appears to suppress the proliferation of fibroblast and thus may provide an effective treatment strategy in glaucoma filtering surgery.


[Nature and store of fatty acid lipids in the blood of newborn calves with dyspepsia].
The content of fatty acids of lipids extracted from the whole blood as well as from erythrocytes, leucocytes, plasma and serum samples of newborn dyspeptic calves were investigated for the first time. Twenty three (23) saturated, mono-non-saturated and poly-non-saturated fatty acids were detected. Native, palmitoleic, stearic, oleic, linoleic and arachidonic fatty acids, are the main components of the whole blood lipid fraction and its components. The fatty acids found in lipids and other components of the whole blood in the samples of dyspeptic and healthy calves are the same, their ratios, however, are different. The decrease in the nonsaturated fatty acids content and its increase in saturated fatty acids are considerable. The saturation coefficient is different in native blood lipids, erythrocytes, leukocytes, serum and plasma.


Improving Uptake and Sustainability of Sanitation Interventions in Timor-Leste: A Case Study.
Open defecation (OD) is still a significant public health challenge worldwide. In Timor-Leste, where an estimated 20% of the population practiced OD in 2017, increasing access and use of improved sanitation facilities is a government priority. Community-led total sanitation (CLTS) has become a popular strategy to end OD since its inception in 2000, but evidence on the uptake of CLTS and related interventions and the long-term sustainability of OD-free (ODF) communities is limited. This study utilized a mixed-methods approach, encompassing quantitative monitoring and evaluation data from water, sanitation, and hygiene (WASH) agencies, and semi-structured interviews with staff working for these organizations and the government Department of Environmental Health, to examine sanitation interventions in Timor-Leste. Recommendations from WASH practitioners on how sanitation strategies can be optimized to ensure ODF sustainability are presented. Whilst uptake of interventions is generally good in Timor-Leste, lack of consistent monitoring and evaluation following intervention delivery may contribute to the observed slippage back to OD practices. Stakeholder views suggest that long-term support and monitoring after ODF certification are needed to sustain ODF communities.


Dynamic Reconfiguration of Visuomotor-Related Functional Connectivity Networks.
Cognitive functions arise from the coordination of large-scale brain networks. However, the principles governing interareal functional connectivity dynamics (FCD) remain elusive. Here, we tested the hypothesis that human executive functions arise from the dynamic interplay of multiple networks. To do so, we investigated FCD mediating a key executing function, known as arbitrary visuomotor mapping, using brain connectivity analyses of high-gamma activity recorded using MEG and intracranial EEG. Visuomotor mapping was found to arise from the dynamic interplay of three partly overlapping cortico-cortical and cortico-subcortical functional connectivity (FC) networks. First, visual and parietal regions coordinated with sensorimotor and premotor areas. Second, the dorsal frontoparietal circuit together with the sensorimotor and associative frontostriatal networks took the lead. Finally, cortico-cortical interhemispheric coordination among bilateral sensorimotor regions coupled with the left frontoparietal network and visual areas. We suggest that these networks reflect the processing of visual information, the emergence of visuomotor plans, and the processing of somatosensory reafference or action's outcomes, respectively. We thus demonstrated that visuomotor integration resides in the dynamic reconfiguration of multiple cortico-cortical and cortico-subcortical FC networks. More generally, we showed that visuomotor-related FC is nonstationary and displays switching dynamics and areal flexibility over timescales relevant for task performance. In addition, visuomotor-related FC is characterized by sparse connectivity with density <10%. To conclude, our results elucidate the relation between dynamic network reconfiguration and executive functions over short timescales and provide a candidate entry point toward a better understanding of cognitive architectures. Executive functions are supported by the dynamic coordination of neural activity over large-scale networks. The properties of large-scale brain coordination processes, however, remain unclear. Using tools combining MEG and intracranial EEG with brain connectivity analyses, we provide evidence that visuomotor behaviors, a hallmark of executive functions, are mediated by the interplay of multiple and spatially overlapping subnetworks. These subnetworks span visuomotor-related areas, the cortico-cortical and cortico-subcortical interactions of which evolve rapidly and reconfigure over timescales relevant for behavior. Visuomotor-related functional connectivity dynamics are characterized by sparse connections, nonstationarity, switching dynamics, and areal flexibility. We suggest that these properties represent key aspects of large-scale functional networks and cognitive architectures.


Treatment of rare factor deficiencies other than hemophilia.
The deficiency of fibrinogen, prothrombin, factor V (FV), FVII, FVIII, FIX, FX, FXI, and FXIII, called rare coagulation disorders (RCDs), may result in coagulopathies leading to spontaneous or posttrauma and postsurgery hemorrhages. RCDs are characterized by a wide variety of symptoms, from mild to severe, which can vary significantly from 1 disease to another and from 1 patient to another. The most typical symptoms of all RCDs are mucosal bleedings and bleeding at the time of invasive procedures, whereas other life-threatening symptoms such as central nervous system bleeding and hemarthroses are mostly present only in some deficiencies (afibrinogenemia, FX, and FXIII). At variance with hemophilia A and B and von Willebrand disease, RCDs are much less prevalent, ranging from 1 case in 500 000 to 1 in 2 million in the general population. Their clinical heterogeneity associated with the low number of patients has led to a delay in the development of appropriate therapies. Indeed, a similar heterogeneity can also be found in the treatment products available, ranging from the specific recombinant proteins to treat FVII- and FXIII-deficient patients to the complete absence of specific products to treat patients with FII or FV deficiencies, for whom prothrombin complex concentrates or fresh frozen plasma are, to date, the only option. The recent development of novel hemostatic approaches for hemophilia, such as the use of nonsubstitutive therapy as RNA interference, anti-tissue factor pathway inhibitor, and the gene therapy aimed at improving the patient's quality of life may also have an important role in the treatment of patients with RCDs in the future.


Genes required for B cell development.
Mutations in a variety of genes can cause congenital agammaglobulinemia and a failure of B cell development. The currently known genes encode components of the pre-B cell receptor or proteins that are activated by cross-linking of the pre-B cell receptor. Defects in these genes result in a block in B cell differentiation at the pro-B to pre-B cell transition. A patient with a translocation involving a previously unknown gene, LRRC8, demonstrated a block at exactly the same point in B cell differentiation (see the related article beginning on page 1707). It will be interesting to determine whether the protein encoded by this gene interacts with the pre-B cell receptor signal transduction pathway or is involved in a new pathway.


Cardiovascular response to static exercise in the conscious cat.
A chronic, unanesthetized cat preparation was used as an experimental model for the study of cardiovascular response to static exercise. Seven cats were operantly conditioned to hold a bar with their right forelimb against increasing resistance for 15 seconds. The exercise regimen lasted from 3 to 6 months. The cats were instrumented with a left ventricular pressure transducer and a left atrial catheter. With exercise, heart rate (HR, + 10%), left ventricular systolic pressure (LVSP, + 16%), and maximal rate of pressure development (LV dp/dt, + 15%) increased significantly. The rise in HR began prior to the onset of exercise and reached peak in less than 5 seconds and then decreased to preexercise levels, although LVSP and LV dp/dt remained elevated during exercise. The magnitude of the LVSP response (range 23 to 31 mmHg) was constant after 2 weeks of training even though the exercise intensity was increased 200 g to 700 g. After 3 months of training, the cats were exercised at the intensity first observed to induce a significant LVSP response. Peak HR, LVSP, and LV dp/dt were significantly reduced. Selective autonomic blockade with propranolol, atropine, and combined atropine-propranolol was utilized to elucidate the role of the autonomic nervous system in the cardiovascular responses that occur during voluntary static exercise. The increased HR in response to exercise was mediated primarily by the parasympathetic nervous system, whereas the increases in LV max dp/dt were mediated by the sympathetic nervous system.


Effects of a quantitative trait locus for increased muscularity on carcass traits measured by subjective conformation and fat class scores and video image analysis in crossbred lambs.
A quantitative trait locus (QTL) for increased loin muscularity (TM-QTL) has previously been identified in purebred Texel sheep. Crossbred lambs born out of Mule ewes mated to heterozygous Texel sires for the TM-QTL were evaluated for a range of carcass traits. Lambs were genotyped and classified as carriers (n = 62) of a single copy of the TM-QTL and non-carriers (n = 49). In this study, the effects of the TM-QTL on carcass attributes were investigated using subjective classification scores for conformation and fatness, and measurements from a video image analysis (VIA) system. In addition, refined prediction equations to estimate weights of primal joints (leg, chump, loin, breast and shoulder) were obtained by calibrating the VIA system against computer tomography (CT) measurements in the loin region. The new refined prediction models increased the accuracy of prediction of all primal cuts on an average of 16% compared to previously derived standard VIA prediction equations. The coefficient of determination (R2) of the VIA system to predict in vivo CT measurements ranged from 0.39 to 0.72 for measurements of Musculus longissimus lumborum (MLL) area, width and depth, lumbar spine length, loin muscle volume and loin muscularity index. Using VIA estimates of CT-measured loin muscle traits, a significant increase in depth (+2.7%) of the MLL was found to be associated with the TM-QTL. Conformation and fatness scores and the shape of the carcass measured as individual lengths, widths and areas by VIA were not significantly influenced by the TM-QTL. Primal meat yields estimated using both standard and refined VIA prediction equations were not significantly affected by the TM-QTL. However, carcass 'compactness' was found to have significantly increased in carrier lambs. The weight of the dissected MLL estimated using VIA information was greater (+2.6%) for carriers compared to non-carriers. To conclude, neither the current industry carcass evaluation system for conformation and fatness nor the standard VIA system is able to identify the effect of the TM-QTL in the loin region in the moment. However, the calibration of the VIA system against CT measurements resulted in improved VIA prediction equations for primal meat yields and also showed moderate potential to estimate loin muscle traits measured by CT and to detect, partially, the effect of the TM-QTL on these traits.


Variants of intestinal metaplasia in the evolution of chronic atrophic gastritis and gastric ulcer. A follow up study.
A follow up study with biopsy was initiated in 1982 to define the relations between variants of intestinal metaplasia and the evolution of chronic atrophic gastritis and gastric ulcer. All patients (58 with chronic atrophic gastritis and 66 with gastric ulcer) had intestinal metaplasia at the start of the study. In the six year period to 1988 a total of 241 biopsies were performed on the patients with chronic atrophic gastritis and 243 on the patients with gastric ulcer. Initially, 81% of the patients with chronic atrophic gastritis presented with type I intestinal metaplasia and 14% with type III intestinal metaplasia. During follow up type I was predominant, often associated with grades 2 and 3 active disease (81%) and 45% of these patients reverted to a non-intestinal metaplasia status by the third year of follow up. In contrast, type III metaplasia was more common in the absence of appreciable inflammation (78% of biopsy specimens), being persistent in five of seven patients in the third year of follow up, and was found to be associated with dysplasia in three of these patients. Similarly, the initial biopsy specimen showed type I metaplasia in most patients with gastric ulcer (82%) and type III in only 4%. Type I metaplasia was also predominant in these patients (80%), particularly in active disease (68%), gradually regressing with healing. In contrast, type III was associated with delayed ulcer healing and reactivation (75%; six of eight patients). We conclude that (a) type I is a short term reactive process which regresses with healing; (b) type III is related to prolonged injury and chronicity and may regress or progress to dysplasia; (c) persistent and more immature forms of metaplasia may carry an increased risk of malignancy.


Counteracting obstacles with optimistic predictions.
This research tested for counteractive optimism: a self-control strategy of generating optimistic predictions of future goal attainment in order to overcome anticipated obstacles in goal pursuit. In support of the counteractive optimism model, participants in 5 studies predicted better performance, more time invested in goal activities, and lower health risks when they anticipated high (vs. low) obstacles in pursuing their goals. These predictions in turn motivated pursuing the goals. These studies further revealed that emphasizing accuracy in predictions reverses the effect of anticipated obstacles on predictions and negatively affects the process of overcoming obstacles in goal pursuit.


Antiviral prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection.
Chronic hepatitis B virus (HBV) carriers are at considerable risk of reactivation of HBV infection when undergoing chemotherapy or immunosuppressive therapy. Complications of HBV reactivation, including asymptomatic elevation of HBV DNA levels, acute hepatitis, acute liver failure, and delays or dose reductions in chemotherapy, are avoidable with appropriate prophylactic oral antiviral therapy. This article reviews evidence for and presents a grade A recommendation supporting primary prophylaxis among HBV carriers with lamivudine. The dose and duration of prophylaxis, risk of lamivudine resistance, and future directions of prophylactic therapy for HBV reactivation during chemotherapy are discussed. Recommendations are suggested based on expert opinion for prophylaxis with the combination of lamivudine plus adefovir or with entecavir as alternative antiviral strategies that substantially reduce or avoid the risk of HBV antiviral drug resistance.


Surgical management of chronic hidradenitis suppurativa of the perineum.
Two cases of chronic hidradenitis suppurativa of the perineum are presented. Both patients suffered through many years of discomfort and social isolation, undergoing multiple temporizing procedures. The treatment course pursued is described in detail. It is hoped that a greater appreciation of the disabling nature of this disease will lead to earlier, definitive therapy.


The 1998 Moyer Award. Characteristics of thrombospondin-1 and its cysteine-serine-valine-threonine-cysteine-glycine receptor in burn wounds.
Thrombospondin-1 (TSP-1), an adhesive glycoprotein, plays an important role in platelet adhesion, inflammation, cell-to-cell interaction, and angiogenesis. TSP-1 is expressed by endothelial cells, fibroblasts, and macrophages. TSP-1's unique cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) specific receptor plays an important role in the binding and modulation of cellular adhesion and invasion. This article histologically and quantitatively evaluates TSP-1 and its CSVTCG receptor in adult burn wounds over time. Tissue was obtained from burn wounds on several days and samples that were 5 microns thick were placed on slides. Expression of TSP-1 and its CSVTCG receptor were evaluated immunohistochemically and quantitated by computer image analysis in units of absorbance. Immunoglobin G (IgG) (negative) controls were performed and subtracted from the TSP-1 sample to eliminate background absorbance readings. Serum (negative) control was used for the CSVTCG receptor. Platelet concentrates were used as the positive control. A quantitative examination of the results yielded the following information, expressed as absorbance +/- standard error of the mean: TSP-1: day 1, 62.0 +/- 10.13; day 3, 76.2 +/- 6.90; day 5, 36.0 +/- 3.96; day 7, 60.4 +/- 5.67; and day 9, 29.5 +/- 2.91. TSP-1 displays an early peak, followed by a steep decrease over the time period studied. The readings for the CSVTCG receptor are as follows: day 1, 33.8 +/- 1.87; day 3, 34.5 +/- 5.39; day 7, 39.1 +/- 1.93; day 21, 39.1 +/- 1.93; day 28, 34.8 +/- 3.67. In contrast, the CVSTCG receptor continues to be present in the wound over time. Histologic findings are reported, and photographs and a histopathologic analysis are included. The information presented in this article leads to the conclusion that temporal and histologic differences exist in the localization and expression of TSP-1 and its CSVTCG receptor. TSP-1 is up-regulated in injured tissues immediately after the injury; it is rapidly down-regulated as the tissue heals. In contrast, the levels of the CSVTCG receptor remain relatively constant during the healing process. These data are consistent with TSP-1's known role in cell-to-cell interaction, including the modulation of the growth factor and protease activity.


An Increase in Mucin2 Expression Is Required for Colon Cancer Progression Mediated by L1.
An induction in the expression of the cell adhesion receptor L1, a Wnt target gene, is a characteristic feature of Wnt/β-catenin activation in colon cancer cells at later stages of the disease. We investigated the proteins secreted following L1 expression in colon cancer cells and identified Mucin2 among the most abundant secreted proteins. We found that suppressing Mucin2 expression in L1-expressing colon cancer cells inhibits cell proliferation, motility, tumorigenesis, and liver metastasis. We detected several signaling pathways involved in Mucin2 induction in L1-expressing cells. In human colon cancer tissue, Mucin2 expression was significantly reduced or lost in the adenocarcinoma tissue, while in the mucinous subtype of colon cancer tissue, Mucin2 expression was increased. An increased signature of L1/Mucin2 expression reduced the survival rate of human colon cancer patients. Thus, induction of Mucin2 expression by L1 is required during mucinous colon cancer progression and can serve as a marker for diagnosis and a target for therapy.


Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases.
Although the majority of mesenchymal lesions of the gastrointestinal tract are neoplastic in nature, nonneoplastic reactive processes may involve the gastrointestinal tract and mesentery, causing diagnostic confusion with more aggressive neoplasms, such as fibromatosis or gastrointestinal stromal tumors. In this study, we report a series of fibroinflammatory lesions of the gastrointestinal tract that we think represent a relatively cohesive group of tumors and describe the clinical and pathologic features of this entity, which we have termed "reactive nodular fibrous pseudotumor." The tumors affected five patients (four male and one female patient) who ranged in age from 48 to 71 years (mean 56 years). Two patients presented with acute abdominal pain without a significant past medical history, two had incidental lesions discovered during evaluation for other medical conditions, and one was found to have an abdominal mass. Three patients had a history of abdominal surgery. The tumors were multiple in three patients and solitary in two patients. In four cases, at least one of the tumors involved the small intestine or colon, and the lesion was confined to the peripancreatic soft tissue in one case. The tumors were firm, tan-white, ranged in size from 4.3 to 6.5 cm in greatest dimension, and were grossly well circumscribed. All of the lesions were of low to moderate cellularity and composed of stellate or spindled fibroblasts arranged haphazardly or in intersecting fascicles. Three cases had microscopically infiltrative borders. The stroma was rich in collagen, which was wire-like, keloidal, or hyalinized. Intralesional mononuclear cells were sparse but were more numerous peripherally and frequently arranged in lymphoid aggregates. Immunohistochemical stains demonstrated that all of the tumors stained for vimentin, 80% stained for CD117 or muscle specific actin, 60% stained for smooth muscle actin or desmin, and none of the tumors stained for CD34, S-100 protein, or anaplastic lymphoma kinase-1. Follow-up information was available in all cases: four patients had no residual disease following surgical resection (mean follow-up 16.3 months) and one patient who had an incomplete surgical resection had stable disease at 26 months. In summary, we report a series of distinct intraabdominal fibroinflammatory pseudotumors that we have collectively termed "reactive nodular fibrous pseudotumors." These lesions are uncommon and may infiltrate the bowel wall, thereby mimicking primary bowel neoplasms or intraabdominal fibromatosis. Recognition of these nonneoplastic lesions is important, as they pursue a benign clinical course, but may be confused with other mesenchymal neoplasms that require more aggressive treatment.


Synaptic transmission between dorsal root ganglion and dorsal horn neurons in culture: antagonism of monosynaptic excitatory postsynaptic potentials and glutamate excitation by kynurenate.
Intracellular recording techniques have been used to provide information on the identity of excitatory sensory transmitters released at synapses formed between dorsal root ganglion (DRG) and dorsal horn neurons maintained in cell culture. Explants of embryonic rat DRG were added to dissociated cultures of embryonic dorsal horn neurons and synaptic potentials were recorded intracellularly from dorsal horn neurons after DRG explant stimulation. More than 80% of dorsal horn neurons within 1 mm of DRG explants received at least one fast, DRG-evoked, monosynaptic input. In the presence of high divalent cation concentrations, the acidic amino acid receptor agonists, L-glutamate, kainate, and quisqualate excited all dorsal horn neurons which received a monosynaptic DRG neuron input, whereas aspartate and N-methyl-D-aspartate (NMDA) had little or no action. Several compounds reported to antagonize the actions of acidic amino acids were tested for their ability to block DRG-evoked synaptic potentials and glutamate-evoked responses in dorsal horn neurons. 2-Amino-5-phosphonovalerate, a selective NMDA receptor antagonist, was relatively ineffective at antagonizing DRG-evoked synaptic potentials and glutamate-evoked responses. In contrast, kynurenate was found to be a potent antagonist of amino acid-evoked responses and of synaptic transmission at all DRG-dorsal horn synapses examined. The blockade of synaptic transmission by kynurenate appeared to result from a postsynaptic action on dorsal horn neurons. These findings indicate that glutamate, or a glutamate-like compound, but not aspartate, is the excitatory transmitter that mediates fast excitatory postsynaptic potentials at the DRG-dorsal horn synapses examined in this study.


The spatial distribution of inhibition of return.
Inhibition of return (IOR) refers to the finding that response times (RTs) are typically slower for targets at previously attended (cued) locations than for targets at novel (uncued) locations. Although previous research has indicated that IOR may spread beyond a cued location, the present study is the first to examine the spatial distribution of IOR with high spatial resolution over a large portion of the central visual field. This was done by using a typical IOR procedure (cue, delay, target) with 4 cue locations and 441 target locations (each separated by 1 degree of visual angle). The results indicate that IOR spreads beyond the cued location to affect the cued hemifield. However, the cues also produced a gradient of RTs throughout the visual field, with inhibition in the cued hemifield gradually giving way to facilitation in the hemifield opposite the cue.


Coronary revascularization trends in the United States, 2001-2008.
Coronary revascularization is among the most common hospital-based major interventional procedures performed in the United States. It is uncertain how new revascularization technologies, new clinical evidence from trials, and updated clinical guidelines have influenced the volume and distribution of coronary revascularizations over the past decade. To examine national time trends in the rates and types of coronary revascularizations. A serial cross-sectional study with time trends of patients undergoing coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions (PCIs) between 2001 and 2008 at US hospitals in the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, which reports inpatient coronary revascularizations. These data were supplemented by Medicare outpatient hospital claims. Annual procedure rates of coronary revascularizations, CABG surgery, and PCI. A 15% decrease (P < .001) in the annual rate of coronary revascularizations was observed from 2001-2002 to 2007-2008. The annual CABG surgery rate decreased steadily from 1742 (95% confidence interval [CI], 1663-1825) CABG surgeries per million adults per year in 2001-2002 to 1081 (95% CI, 1032-1133) CABG surgeries per million adults per year in 2007-2008 (P < .001), but PCI rates did not significantly change (3827 [95% CI, 3578-4092] PCI per million adults per year in 2001-2002 vs 3667 [95% CI, 3429-3922] PCI per million adults per year in 2007-2008, P = .74). Between 2001 and 2008, the number of hospitals in the Nationwide Inpatient Sample providing CABG surgery increased by 12% (212 in 2001 vs 241 in 2008, P = .03), and the number of PCI hospitals increased by 26% (246 in 2001 vs 331 in 2008, P < .001). The median CABG surgery caseload per hospital decreased by 28% (median [interquartile range], 253 [161-458] in 2001 vs 183 [98-292] in 2008; P < .001) and the number of CABG surgery hospitals providing fewer than 100 CABG surgeries per year increased from 23 (11%) in 2001 to 62 (26%) in 2008 (P < .001). In US hospitals between 2001 and 2008, a substantial decrease in CABG surgery utilization rates was observed, but PCI utilization rates remained unchanged.


Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.
Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects. Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts. In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells. These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.


Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.
Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented. Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs. Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%). The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC. Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.


Frequency combs in a microring optical parametric oscillator.
We report the soliton frequency comb generation in microring optical parametric oscillators operating in the downconversion regime and with the simultaneous presence of the χ(2) and Kerr nonlinearities. The combs are studied considering a typical geometry of a bulk LiNbO3 toroidal resonator with the normal group velocity dispersion spanning an interval between the pump and the downconverted signal. We have identified critical power signaling a transition between the relatively low pump power predominantly χ(2) combs and the high pump power ones shaped by the competition between the χ(2) and Kerr nonlinearities.


Implicit acquisition of grammars with crossed and nested non-adjacent dependencies: investigating the push-down stack model.
A recent hypothesis in empirical brain research on language is that the fundamental difference between animal and human communication systems is captured by the distinction between finite-state and more complex phrase-structure grammars, such as context-free and context-sensitive grammars. However, the relevance of this distinction for the study of language as a neurobiological system has been questioned and it has been suggested that a more relevant and partly analogous distinction is that between non-adjacent and adjacent dependencies. Online memory resources are central to the processing of non-adjacent dependencies as information has to be maintained across intervening material. One proposal is that an external memory device in the form of a limited push-down stack is used to process non-adjacent dependencies. We tested this hypothesis in an artificial grammar learning paradigm where subjects acquired non-adjacent dependencies implicitly. Generally, we found no qualitative differences between the acquisition of non-adjacent dependencies and adjacent dependencies. This suggests that although the acquisition of non-adjacent dependencies requires more exposure to the acquisition material, it utilizes the same mechanisms used for acquiring adjacent dependencies. We challenge the push-down stack model further by testing its processing predictions for nested and crossed multiple non-adjacent dependencies. The push-down stack model is partly supported by the results, and we suggest that stack-like properties are some among many natural properties characterizing the underlying neurophysiological mechanisms that implement the online memory resources used in language and structured sequence processing.


A typology of sick-listed claimants to improve communication skills for social insurance physicians during medical disability assessment interviews.
Role play with standardised simulated patients is often included in communication training. However, regarding physician-patient encounters in medical disability assessment interviews it is unclear what should be included in the scenarios for actors. The first objective of this study was to determine which types of medical disability claimants can be distinguished based on behavioural determinants. The second objective was to determine if these types of claimants differed in their perception of communication behaviour and their satisfaction with the communication with physicians. Questionnaire data were collected from 56 Dutch claimants for 13 behavioural determinants before their assessment interview, and for 12 behavioural and satisfaction variables afterwards. For the first objective cluster analyses were performed and for the second objective linear regression analyses were performed. The results showed that three types of claimants could be distinguished: insecure support-seeking claimants, confident claimants, and socially isolated claimants. Overall, claimants were positive about the communication with the physician: insecure support-seeking claimants were satisfied and confident claimants were highly satisfied, but socially isolated claimants were unsatisfied. Scenarios for standardised simulated patients should include different types of claimants. In training, special attention should be given to communication with socially isolated claimants.


Fixation, mounting and sealing with nail polish of cell specimens lead to incorrect FRET measurements using acceptor photobleaching.
Fluorescence resonance energy transfer (FRET) is a technique used for the study of functional interactions between molecules. The intimate vicinity between two fluorescent molecules (FRET-pair; donor and acceptor) allows for an energy transfer, which can be directly calculated as the so called FRET efficiency. This technique is used in fixed as well as living cells. Here we show first, measured by the FRET technique, that the ICln ion channel is transposed from the cytosol towards the cellular membrane in HEK cells after swelling, and second, that the calculation of the FRET efficiency by de-quenching the donor cyan-fluorescent-protein (CFP) emission due to acceptor-photobleaching leads to erroneous estimate of the FRET efficiency in fixed, mounted and sealed specimens. The acceptor photobleaching leads to a modification of the donor cyan-fluorescent-protein, which shows then a strong emission, thus mimicking functional interaction between CFP (donor) and yellow-fluorescent-protein (YFP; acceptor). Moreover, the procedure of acceptor photobleaching masks physiological (non random) interaction between molecules within the fixed, mounted and sealed cell. We show that no artifactual CFP modifications arise when using the acceptor photobleaching technique under in vivo conditions, and we offer strategies to minimize erroneous FRET efficiency calculations if cells need to be fixed.


Improved glycemic control in C57Bl/KsJ (db/db) mice after treatment with the thermogenic beta-adrenoceptor agonist, BRL 26830.
BRL 26830, (R*,R*)-(+/-)-methyl-4-(2-[(2-hydroxy-2-phenylethyl)amino]propyl)-benzoa te, is a new type of beta-adrenoceptor receptor agonist that combines antihyperglycemic and thermogenic properties. In C57Bl/KsJ db/db mice, treatment with BRL 26830 (50 mg of the hemifumarate salt/kg diet) decreased blood glucose concentration and normalized water intake. As judged by the normalization of polydipsia, BRL 26830 was effective within 2 days and the effect was maintained throughout a treatment period of up to 11 wk. Treatment of db/db mice with BRL 26830 resulted in an increase in both plasma and pancreatic insulin concentrations and a partial restoration of first-phase insulin secretion by the isolated, perfused pancreas in response to a high (16.7 mM) glucose pulse. Given acutely, BRL 26830 increased energy expenditure in both fed and fasted db/db mice. When given chronically, BRL 26830 increased significantly the dietary and thermoregulatory component of metabolic rate. It is suggested that the antidiabetic and thermogenic properties of BRL 26830 are linked and that blood glucose acts either directly or indirectly as a substrate for thermogenesis.


Single cell analysis facilitates staging of Blimp1-dependent primordial germ cells derived from mouse embryonic stem cells.
The cell intrinsic programming that regulates mammalian primordial germ cell (PGC) development in the pre-gonadal stage is challenging to investigate. To overcome this we created a transgene-free method for generating PGCs in vitro (iPGCs) from mouse embryonic stem cells (ESCs). Using labeling for SSEA1 and cKit, two cell surface molecules used previously to isolate presumptive iPGCs, we show that not all SSEA1+/cKit+ double positive cells exhibit a PGC identity. Instead, we determined that selecting for cKit(bright) cells within the SSEA1+ fraction significantly enriches for the putative iPGC population. Single cell analysis comparing SSEA1+/cKit(bright) iPGCs to ESCs and embryonic PGCs demonstrates that 97% of single iPGCs co-express PGC signature genes Blimp1, Stella, Dnd1, Prdm14 and Dazl at similar levels to e9.5-10.5 PGCs, whereas 90% of single mouse ESC do not co-express PGC signature genes. For the 10% of ESCs that co-express PGC signature genes, the levels are significantly lower than iPGCs. Microarray analysis shows that iPGCs are transcriptionally distinct from ESCs and repress gene ontology groups associated with mesoderm and heart development. At the level of chromatin, iPGCs contain 5-methyl cytosine bases in their DNA at imprinted and non-imprinted loci, and are enriched in histone H3 lysine 27 trimethylation, yet do not have detectable levels of Mvh protein, consistent with a Blimp1-positive pre-gonadal PGC identity. In order to determine whether iPGC formation is dependent upon Blimp1, we generated Blimp1 null ESCs and found that loss of Blimp1 significantly depletes SSEA1/cKit(bright) iPGCs. Taken together, the generation of Blimp1-positive iPGCs from ESCs constitutes a robust model for examining cell-intrinsic regulation of PGCs during the Blimp1-positive stage of development.


Branches of the thoracic sympathetic trunk in the human fetus.
The segmental organization of the thoracic sympathetic trunk and all its ramifications was studied in 6 human fetuses (16-22 weeks) by means of the acetylcholinesterase in toto staining method. Each trunk was divided into 12 sympathetic segments. A segment is defined as that part of the sympathetic trunk which is connected via its rami communicantes with one spinal nerve, without discriminating between grey and white rami. The diameter of the rami communicantes and their direction towards the spinal nerves are variable. The number of peripheral segmental ramifications of the trunk is much larger than assumed previously. Each thoracic sympathetic segment gives off at least 4-5 nerves. Three categories of nerves are discerned: (1) large splanchnic rootlets confined to the greater, lesser and least thoracic splanchnic nerves, (2) medium-sized splanchnic nerves directed towards thoracic viscera, some of which give off branches towards costovertebral joint plexuses and, described for the first time in man, (3) small nerves which ramify extensively and form nerve plexuses in the capsule of the costovertebral joints. The majority of the ramifications is formed by the nerves of the third category. The existence of Kuntz's nerve, connecting the 2nd intercostal nerve and 1st thoracic spinal nerve, is confirmed in four specimens. The nerve plexuses of the costovertebral joints receive a segmentally organized innervation: they receive their input from the neighbouring sympathetic segment and the one cranial to it. It is concluded that the thoracic sympathetic branches in man show a complex, segmentally organized pattern and may have a considerable component of somatosensory nerve fibers. The complex relationships must be taken into account in surgical sympathectomies.


Adversarial Attacks on Time Series.
Time series classification models have been garnering significant importance in the research community. However, not much research has been done on generating adversarial samples for these models. These adversarial samples can become a security concern. In this paper, we propose utilizing an adversarial transformation network (ATN) on a distilled model to attack various time series classification models. The proposed attack on the classification model utilizes a distilled model as a surrogate that mimics the behavior of the attacked classical time series classification models. Our proposed methodology is applied onto 1-nearest neighbor dynamic time warping (1-NN DTW) and a fully convolutional network (FCN), all of which are trained on 42 University of California Riverside (UCR) datasets. In this paper, we show both models were susceptible to attacks on all 42 datasets. When compared to Fast Gradient Sign Method, the proposed attack generates a larger faction of successful adversarial black-box attacks. A simple defense mechanism is successfully devised to reduce the fraction of successful adversarial samples. Finally, we recommend future researchers that develop time series classification models to incorporating adversarial data samples into their training data sets to improve resilience on adversarial samples.


Phosphorylation at Thr167 is required for Schizosaccharomyces pombe p34cdc2 function.
Eukaryotic cell cycle progression requires the periodic activation and inactivation of a protein-serine/threonine kinase which in fission yeast is encoded by the cdc2+ gene. The activity of this gene product, p34cdc2, is controlled by numerous interactions with other proteins and by its phosphorylation state. In fission yeast, p34cdc2 is phosphorylated on two sites, one of which has been identified as Tyr15. Dephosphorylation of Tyr15 regulates the initiation of mitosis. To understand more completely the regulation of p34cdc2 kinase activity, we have identified the second site of phosphorylation as Thr167, a residue conserved amongst all p34cdc2 homologues. By analysing the phenotypes of cells expressing various position 167 mutations and performing in vitro experiments, we establish that Thr167 phosphorylation is required for p34cdc2 kinase activity at mitosis and is involved in the association of p34cdc2 with cyclin B. Dephosphorylation of Thr167 might also play a role in the exit from mitosis.


Modulation of Gr1low monocyte subset impacts insulin sensitivity and weight gain upon high-fat diet in female mice.
Blood monocytes are expanded during obesity. However, the differential contribution of monocyte subsets in obesity-related metabolic disorders remains unknown. The aim of the study was to define the role of the Gr1low monocyte subset upon high-fat diet (HFD). We used transgenic female mouse models allowing the modulation of circulating Gr1low monocyte number (decreased number in CX3CR1-/- mice and increased number in CD11c-hBcl2 mice) and studied obesity upon HFD. We reported here that HFD induced monocytosis in mice, preferentially due to Gr1low monocyte expansion, and was associated with a specific upregulation of CD11c on that subset. Using mice models with altered Gr1low monocyte number, we found a striking correlation between Gr1low monocytes, bodyweight (BW) and insulin resistance (RT) status. Indeed, CX3CR1-/- female mice, with reduced Gr1low monocytes upon HFD, showed increased RT and a pro-inflammatory profile of the adipose tissue (AT) despite a lower BW. Conversely, mice expressing the anti-apoptotic gene hBcl2 in CD11c-expressing cells have increased Gr1low monocytes, higher insulin sensitivity upon HFD and an anti-inflammatory profile of the AT. Finally, increasing Gr1low monocytes in Gr1low-defective CX3CR1-/- mice rescued BW loss in these mice. By using transgenic female mice and adoptive transfer experiments, we established the evidence for a correlation between Gr1low monocyte subset and weight gain and RT. Hence, this specific Gr1low monocyte subset could be used as a target for acting on AT inflammation and RT.


Costimulation blockade: towards clinical application.
Organ transplantation is an increasingly successful therapy for many forms of organ failure, but its success depends upon drug therapies to prevent immunologic destruction of the transplanted organ also known as rejection. Most therapies designed to prevent rejection alter the immune system in a rather broad, antigen independent way, and thus alter protective immunity as well as immune responses directed against the transplanted organ. Over the past 3 decades, however, it has been realized that a class of surface molecules known as costimulatory receptors are required to generate a fully productive immune response, and that blockade of these receptors during allo-antigen recognition can be used to influence the immune system's future response to that particular allo-antigen. Costimulation blockade has thus been developed as a specific field of interest towards achieving improved antigen specific control over transplant rejection while minimizing broad attenuation of protective immunity seen with conventional immunosuppressives. This field has grown rapidly in the past decade and is now poised to become a valuable therapeutic option for transplant clinicians. This review will outline the basic premise of costimulation biology, review the seminal experimental basis for its use in preventing organ rejection, and discuss the relevant data derived from its initial use in clinical transplant trials. Specific attention will be focused on two major costimulatory pathways, the CD28/CD80-CD86 and the CD40-CD154 pathways, and the clinically applicable data supporting their validity as therapeutic targets. Newly discovered costimulatory pathways will also be discussed as potential therapeutic targets for future clinical drugs.


Synchrony between sensory and cognitive networks is associated with subclinical variation in autistic traits.
Individuals with autistic spectrum disorders exhibit distinct personality traits linked to attentional, social, and affective functions, and those traits are expressed with varying levels of severity in the neurotypical and subclinical population. Variation in autistic traits has been linked to reduced functional and structural connectivity (i.e., underconnectivity, or reduced synchrony) with neural networks modulated by attentional, social, and affective functions. Yet, it remains unclear whether reduced synchrony between these neural networks contributes to autistic traits. To investigate this issue, we used functional magnetic resonance imaging to record brain activation while neurotypical participants who varied in their subclinical scores on the Autism-Spectrum Quotient (AQ) viewed alternating blocks of social and nonsocial stimuli (i.e., images of faces and of landscape scenes). We used independent component analysis (ICA) combined with a spatiotemporal regression to quantify synchrony between neural networks. Our results indicated that decreased synchrony between the executive control network (ECN) and a face-scene network (FSN) predicted higher scores on the AQ. This relationship was not explained by individual differences in head motion, preferences for faces, or personality variables related to social cognition. Our findings build on clinical reports by demonstrating that reduced synchrony between distinct neural networks contributes to a range of subclinical autistic traits.


Reduction of carcinogenic 4(5)-methylimidazole in a caramel model system: influence of food additives.
The effect of various food additives on the formation of carcinogenic 4(5)-methylimidazole (4-MI) in a caramel model system was investigated. The relationship between the levels of 4-MI and various pyrazines was studied. When glucose and ammonium hydroxide were heated, the amount of 4-MI was 556 ± 1.3 μg/mL, which increased to 583 ± 2.6 μg/mL by the addition of 0.1 M of sodium sulfite. When various food additives, such as 0.1 M of iron sulfate, magnesium sulfate, zinc sulfate, tryptophan, and cysteine were added, the amount of 4-MI was reduced to 110 ± 0.7, 483 ± 2.0, 460 ± 2.0, 409 ± 4.4, and 397 ± 1.7 μg/mL, respectively. The greatest reduction, 80%, occurred with the addition of iron sulfate. Among the 12 pyrazines, 2-ethyl-6-methylpyrazine with 4-MI showed the highest correlation (r = -0.8239).


Health-related quality of life in HIV/AIDS patients on antiretroviral therapy at a tertiary care facility in Zimbabwe.
Health-related quality of life (HRQoL) is a broad concept reflecting a patient's general subjective perception of the effect of an illness or intervention on physical, psychological and social aspects of their daily life. HRQoL among patients infected with HIV has become an important indicator of impact of disease and treatment outcomes. A cross-sectional survey was carried out at Chitungwiza Central Hospital, Zimbabwe, to assess HRQoL in patients with HIV/AIDS receiving antiretroviral therapy (ART), using two validated instruments. The HIV/AIDS-targeted quality of life (HAT-QoL) and EuroQoL Five-dimensions-Three-level (EQ-5D-3L) instruments were used to assess HRQoL. Internal consistency reliability and convergent validity of the two instruments were also evaluated. For construct validity, the relationships between HRQoL scores and socio-economic and HIV/AIDS-related characteristics were explored. The median scores for the HAT-QoL dimensions ranged from 33.3 (financial worries) to 100 (HIV mastery). A considerably low HAT-QoL dimension score of 50.0 was observed for sexual function. There were ceiling effects for all HAT-QoL dimension scores except for financial worries and disclosure worries. Floor effects were observed for financial worries and sexual function. The median of the EQ-5D-3L index and visual analogue scale (VAS) was 0.81 and 79.0, respectively. There were no floor or ceiling effects for both the EQ-5D-3L index and VAS. The overall scale Cronbach's alpha was 0.83 for HAT-Qol and 0.67 for EQ-5D-3L. HAT-QoL demonstrated good convergent validity with EQ-5D index (0.58) and VAS (0.40). A higher level of HRQoL was positively and significantly related to income, education and employment. The patients' self-reported HRQoL was generally satisfactory in all the HAT-QoL dimensions as well as the two components on the EQ-5D-3L instrument. The two instruments demonstrated good measurement properties in HIV/AIDS patients receiving ART and have potential for use, alongside biomarkers, in monitoring outcomes of interventions.


Somatic mosaicism in plants with special reference to somatic crossing over.
Plant systems in use for the detection of environmental mutagens appear capable of detecting all types of genetic effects which can be studied in animals. The study of somatic mosaicism, however, is better developed in plants than in higher animals. A case is presented here which shows the ability of plant systems in analyzing a host of genetic end points, including chromosome aberrations like deletions, somatic crossing over, numerical inequality, gene conversion, paramutations and point mutations. The systems in general use utilize certain varieties of Tradescantia, Glycine max, Nicotiana tabacum, Antirrhinum majus, Petunia hybrida, and Arabidopsis thaliana. Heterozygous plants or their homozygous counterparts with gene markers affecting chlorophyll development or anthocyanin in floral parts are exploited in these studies. Mutagens produce different frequencies of different types of spots typical of the mode of action of the agent. Analysis of these parameters may be used to predict, at least qualitatively, the kind of genetic damage that might be produced in man. Besides, one can test the validity of interpretation by traditional progeny tests of plants raised from tissue culture from sectors as in Nicotiana and/or by precursor analysis as done in Antirrhinum. The study of mosaicism in plants offers quite inexpensive, rapid, and reliable tests of mutagenicity at least as a preliminary eukaryotic test system.


[Effect of insulin of frog skeletal muscle respiration].
The respiration of the isolated frog sartorius muscle was measured polarographically. The endogenous respiration was seen to increase by 8 and 6 times in 20 mM KCL and 0.05 mM 2,4-DNP, resp., and by 40 percent in 10mM pyruvate or lactate. Insulin stimulated the endogemous respiration from 27 to 38 mm-3 O2/hr. per gramm of wet weight. In the excess of exogenous lactate and pyruvate, the degree of the insulin stimulated respiration did not change. It is suggested that the increase of the endogenous respiration by insulin cannot be accounted for by the mobilization of the substrate of glycolysis.


Influenza nucleoprotein: promising target for antiviral chemotherapy.
In the search for new anti-influenza agents, the viral polymerase has often been targeted due to the involvement of multiple conserved proteins and their distinct activities. Polymerase associates with each of the eight singled-stranded negative-sense viral RNA segments. These transcriptionally competent segments are coated with multiple copies of nucleoprotein (NP) to form the ribonucleoprotein. NP is an abundant essential protein, possessing operative and structural functions, and participating in genome organization, nuclear trafficking and RNA transcription and replication. This review examines the NP structure and function, and explores NP as an emerging target for anti-influenza drug development, focusing on recently discovered aryl piperazine amide inhibitor chemotypes.


Antihypertensive therapy and the progression of chronic renal disease. Are there renoprotective drugs?
The pathogenesis of hypertensive glomerular injury is complex, involving both hemodynamic and nonhemodynamic factors. One can therefore confidently predict that a wide variety of disparate therapeutic interventions, pharmacologic and nonpharmacologic, may be effective in arresting or slowing progressive glomerular injury. Based on the experimental and clinical literature available to date, it is clear that glomerular capillary hypertension is an important pathogenetic factor in this disease and that lowering of Pgc with antihypertensive drugs is associated with prevention of glomerular injury. Furthermore, the CEI may have a special renoprotective effect compared to other antihypertensive agents, most likely due to their unique renal hemodynamic actions. Pending the results of well-designed clinical trials, converting enzyme inhibitors represent the antihypertensive agents most likely to arrest the progressive decline in renal function observed in patients with hypertension and chronic renal failure. The calcium channel blockers are effective antihypertensive agents in patients with chronic renal failure, but whether they confer specific renoprotective effects remains uncertain. Since a large number of patients with chronic renal failure require more than one antihypertensive drug for adequate blood pressure control it may be of interest to evaluate the benefits of drug combinations. In this regard, it is possible that a combination of a CEI and a CCB may have complimentary effects in protecting the kidney. The development of these new classes of antihypertensive agents has had a major impact on the treatment of patients with chronic progressive renal failure. Future studies will hopefully clarify the optimal antihypertensive therapeutic regimen and allow us to move closer to the goal of eliminating end-stage renal failure.


Investigating the Relationship Between Marital Status and Ethnicity on Neurocognitive Functioning in a Rural Older Population: A Project Frontier Study.
Research indicates being married is related to better physical and psychological health. Little is known regarding the relationship between marital status and neurocognitive functioning and whether it differs based on ethnicity (Hispanic vs. non-Hispanic). This is the first study to examine this relationship in a sample of aging adults in rural Texas. Data from 1864 participants (Mage=59.68, SDage=12.21), who were mostly Hispanic (n=1053), women (n=1295), and married (n=1,125) from Project FRONTIER were analyzed. Neuropsychological testing comprised RBANS, Trails Making Test, and Clock Drawing. Participants were dichotomized, married and unmarried. There was a significant interaction between Hispanic identity and marital status on overall neurocognitive functioning (F(1,1480) =4.79, p < .05, ηp2=.003). For non-Hispanic individuals, married individuals had higher overall neurocognitive functioning compared to unmarried individuals, whereas neurocognitive functioning for Hispanic individuals did not significantly differ between married and unmarried individuals. There were significant main effects as married individuals (M=84.95, SD=15.56) had greater overall neurocognitive functioning than unmarried individuals (M=83.47, SD=15.86; F(1,1480) = 14.67, p < .001, ηp2=.01), Hispanic individuals (M=78.02, SD=14.25) had lower overall neurocognitive functioning than non-Hispanic individuals (M=91.43, SD=15.07; F(1,1480) = 284.99, p < .001, ηp2=.16). Hispanics living in rural areas experience additional stressors that could lead to worse neurocognitive functioning, which is supported by the Lifespan Biopsychosocial Model of Cumulative Vulnerability and Minority Health, which postulates that race/ethnicity/SES-related stressors exacerbate the impact of other life stressors. Reduction of stress on rural Hispanics should be a priority as it could positively affect their neurocognitive functioning.


Factors affecting female sexual well-being: a 5-year follow-up of a randomised clinical trial on post-abortion contraception.
Sexual well-being is associated with general well-being. Several factors, such as overweight, infertility, anxiety and sex hormones, also play a role, but the effects of hormonal contraception remain a point of debate. We characterised the factors associated with sexual well-being in fertile-aged women following induced abortion. A 5-year follow-up of a nested, longitudinal, cohort study examining the effects of routine provision of intrauterine contraception as part of abortion care. Sexual well-being, anxiety and quality of life were assessed annually using validated questionnaires (McCoy Female Sexuality Questionnaire, State-Trait Anxiety Inventory and EuroQoL), along with data on general and reproductive health, and relationship status. Of the 742 women participating in the trial, 290 (39%) provided sufficient follow-up data and were included in this study. Based on trajectories of McCoy scores across the 5-year follow-up, two groups were identified: those with stable and higher (n=223, 76.9%) and those with declining sexual well-being (n=67, 23.1%). Women in the group of declining sexual well-being had significantly higher levels of anxiety and lower quality of life at all time points. They also had chronic diseases more often and were less happy in their relationships. No differences were found in method of contraception when classified as hormonal versus non-hormonal, or long-acting versus short-acting reversible contraception. Lower anxiety and higher quality of life are associated with stable and higher sexual well-being. Method of contraception or relationship status are not associated with sexual well-being during long-term follow-up in fertile-aged women.


Critical weight mediates sex-specific body size plasticity and sexual dimorphism in the yellow dung fly Scathophaga stercoraria (Diptera: Scathophagidae).
Ultimate factors driving insect body size are rather well understood, while-apart from a few model species-the underlying physiological and developmental mechanisms received less attention. We investigate the physiological basis of adaptive size variation in the yellow dung fly Scathophaga stercoraria, which shows pronounced male-biased sexual size dimorphism and strong body size plasticity. We estimate variation of a major physiological threshold, the critical weight, which is the mass at which a larva initiates pupariation. Critical weight was associated with sexual size dimorphism and sex-specific plasticity, and is thus a likely target of selection on adult size. Detailed larval growth trajectories derived from individuals raised at two food and temperature treatments further reveal that sex-specific size plasticity is mediated by faster initial growth of males that later becomes reduced by higher male weight loss during the wandering stage. We further demonstrate that integral growth rates, which are typically calculated as simple ratios of egg-to-adult development time and adult weight, do not necessarily well reflect variation in instantaneous growth rates. We illustrate the importance of detailed assessments of ontogenetic growth trajectories for the understanding of adaptive size variation and discuss the mechanistic basis of size determination in shaping sex-specific phenotypic plasticity.


The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency.
Circulating insulin-like growth factor-I (IGF-I) is predominantly bound in the trimeric complex comprised of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). Circulating concentrations of IGF-I, IGFBP-3 and ALS are believed to reflect the GH secretory status, but the clinical use of ALS determination is not known. We therefore, determined the: 1) hepatosplanchnic release of ALS by liver vein catheterization (n=30); 2) 24-h diurnal variation of ALS (n=8); 3) normal age-related ranges of circulating ALS (n=1158); 4) diagnostic value of ALS in 108 patients with childhood-onset GH deficiency (GHD). We found: 1) no significant arteriovenous gradient over the liver ofALS, IGF-I, and IGFBP-3; 2) the diurnal variation of ALS was 12% (mean coefficient of variation percent); 3) ALS levels increased throughout childhood with maximal levels in puberty, with a subsequent decrease with age in adults; and 4) ALS levels were below -2 SD in 57 of 79 GHD patients (sensitivity 72%) and above 2 SD in 22 of 29 patients with normal GH response (specificity 76%), which was similar, compared with the diagnostic utility of IGF-I and IGFBP-3. Finally, our findings indicate that hepatic ALS production is not measurable by this approach or, alternatively, that the liver is not the primary source of circulating ALS, IGF-I, or IGFBP-3 in humans. In conclusion, we have provided extensive normal data for a novel ALS assay and found that circulating ALS levels exhibit minor diurnal variation. We suggest that ALS determination may be used in future classification of adults suspected of GHD.


Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial.
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes. To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes. This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27 395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017. Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). Risk of ischemic stroke subtypes during follow-up. A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes. For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice. ClinicalTrials.gov identifier: NCT01776424.


The composition of cigarette smoke: a retrospective, with emphasis on polycyclic components.
The difficulties encountered in extrapolating biological activity from cigarette smoke composition provide generally applicable lessons as they are representative of the problems encountered with other complex mixtures. Researchers attempting to assess risk are faced with attempting to interpret data from a number of areas including: tobacco science; smoke/aerosol chemistry specific to tobacco; sophisticated analytical chemistry applications and techniques for trapping, collecting, separating, and quantifying very specific compounds at nanogram to picogram levels; numerous biological testing methodologies; and animal models of tumors and carcinogenesis. Numerous hypotheses have been developed over the past five decades and tested with the technology of the day in attempts to interpret the biological activity of cigarette smoke in relation to the chemistry of this complex mixture. These hypotheses fall into several categories discussed in this review: mechanisms of pyrogenesis of polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke; levels of PAHs in cigarette mainstream smoke (MS) and its tumorigenicity in mouse skin-painting experiments; control of PAH levels in MS; chemical indicators of cigarette smoke condensate (CSC) tumorigenicity; control of levels of MS components partitioned between the vapor phase and particulate phase of MS; tumorigenic threshold limits of CSC and many of its components; tumorigenic aza-arenes in tobacco smoke; MS components reported to be ciliastatic to smokers' respiratory tract cilia; anticarcinogenic tobacco-smoke components. Of 52 hypotheses reviewed in this paper, 15 have excellent data supporting the hypothesis based on today's technology. The remaining 37 hypotheses, although originally plausible, have since become insupportable in light of new and contradictory data generated over the years. Such data were generated sometimes by the original authors of the hypotheses and sometimes by other investigators. The hypotheses presented today are less likely to be supplanted because they are well conceived and have a strong mechanistic basis. The challenge for the future is the generation and interpretation of data relating the chemistry and biological activity associated with the dynamic and complex mixture of tobacco smoke.


Youth experiencing transitional and temporary homelessness: A pilot study.
Homeless youth represent a vulnerable and understudied population, particularly those among them who are hidden, experiencing transitional or temporary homelessness. Little research focuses on this group, including the methods and settings to identify and tailor interventions to their circumstances. Given the immediate risks and possible transition to chronic homelessness, their identification is critical for prevention and intervention efforts. This exploratory pilot study investigated transitional and temporary homelessness among youth. The study demonstrated the ability to identify such participants. Twenty participants completed a survey that measured demographics, behavioral risk factors, and the Brief Symptom Inventory (BSI; Derogatis, 1993). Reports of relationships with parents varied. They included positive maternal relationships, but also concerns about intrafamilial conflict. While frequent change of schools was reported, generally positive feelings toward school were expressed. Social relationships suggest limited exposure to other homeless youth. Some substance abuse was noted, possibly at lower rates than expected for hard drugs. The BSI results are suggestive of health concerns. The study demonstrated that it is possible to capture children experiencing transitional or temporary homelessness in alternative school settings. It is essential that efforts be made to identify them and provide early supports toward preventing chronic homelessness.


An adult norovirus-related encephalitis/encephalopathy with mild clinical manifestation.
Norovirus is an emerging pathogen that causes gastroenteritis outbreaks. Here, we reported an adult female case of norovirus-related encephalitis/encephalopathy (NvREE) with abnormal behaviour, apathy, motor aphasia, bradykinesia and gait disturbance. We treated the patient with intravenous methyl-prednisolone pulse therapy and she recovered quickly. There were slight abnormal signals in the cortex of the opercular part and insula on the MRI fluid-attenuated inversion-recovery (FLAIR) image, generalised slow wave as a background activity in her EEG and cerebrospinal fluid pleocytosis, which restored soon after her recovery. We successfully detected the norovirus genome in stool samples from all seven family members. This is a first case report of an adult NvREE with detection of pathogenic evidence. There could be more cases of NvREE with mild neuropsychiatric symptoms, considering the increasing outbreaks each year.


Ex Vivo Bioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4(+) T Cells from Aviremic Patients.
The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4(+) T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4(+) T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4(+) T cells from aviremic HIV-1(+) patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1(+) antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4(+) T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation.


Morphine-like discriminative stimulus effects of buprenorphine and demethoxybuprenorphine in rats: quantitative antagonism by naloxone.
The interactions between the opioid antagonist naloxone and the opioids morphine, buprenorphine and demethoxybuprenorphine ( DMB ), an acid-catalyzed rearrangement product of buprenorphine, were evaluated quantitatively in rats trained to discriminate between saline and 3.0 mg/kg of morphine using a two-choice, shock avoidance procedure. Dose-effect curves for each of the three agonists were determined alone and in the presence of varying doses of naloxone (0.01-1.0 mg/kg). Buprenorphine and DMB produced dose-related increases in morphine-appropriate responding which plateaued over at least a 30-fold dose-range for each drug. On a molar basis, buprenorphine was approximately 140 times and DMB approximately 45 times more potent than morphine. Naloxone produced parallel shifts in the dose-effect curves for morphine, buprenorphine and DMB . Schild plots derived from the relative shifts in the dose-effect curves yielded regression lines with slopes which were not significantly different from -1, consistent with naloxone acting as a competitive antagonist of each of the three opioids. The apparent pA2 values for naloxone were 7.85 +/- 0.36 against morphine, 7.48 +/- 0.16 against buprenorphine and 7.17 +/- 0.27 against DMB . Because the 95% CLs overlapped for morphine and buprenorphine, but not for morphine and DMB , these results are consistent with the interpretation that naloxone is acting at the same receptor in antagonizing morphine and buprenorphine but naloxone may be acting in a more complex manner in antagonizing DMB . The effectiveness of naloxone in antagonizing equieffective doses of morphine (3.0 mg/kg), buprenorphine (0.03 mg/kg) and DMB (0.1 mg/kg) were also evaluated when naloxone was administered either 0 or 30 min after the agonist.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of synaptic noise and filtering on the frequency response of spiking neurons.
Noise can have a significant impact on the response dynamics of a nonlinear system. For neurons, the primary source of noise comes from background synaptic input activity. If this is approximated as white noise, the amplitude of the modulation of the firing rate in response to an input current oscillating at frequency omega decreases as 1/square root[omega] and lags the input by 45 degrees in phase. However, if filtering due to realistic synaptic dynamics is included, the firing rate is modulated by a finite amount even in the limit omega-->infinity and the phase lag is eliminated. Thus, through its effect on noise inputs, realistic synaptic dynamics can ensure unlagged neuronal responses to high-frequency inputs.


A study of cervical spine kinematics and joint capsule strain in rear impacts using a human FE model.
Many efforts have been made to understand the mechanism of whiplash injury. Recently, the cervical facet joint capsules have been focused on as a potential site of injury. An experimental approach has been taken to analyze the vertebral motion and to estimate joint capsule stretch that was thought to be a potential cause of pain. The purpose of this study is to analyze the kinematics of the cervical facet joint using a human FE model in order to better understand the injury mechanism. The Total Human Model for Safety (THUMS) was used to visually analyze the local and global kinematics of the spine. Soft tissues in the neck were newly modeled and introduced into THUMS for estimating the loading level in rear impacts. The model was first validated against human test data in the literature by comparing vertebrae motion as well as head and neck responses. Joint capsule strain was estimated from a maximum principal strain output from the elements representing the capsule tissues. A rear-end collision was then simulated using THUMS and a prototype seat model, assuming a delta-V of 25 km/h. The trajectory of the vertebrae was analyzed in a local coordinate system defined along the joint surface. Strain growth in the joint capsules was explained, as related to contact events between the occupant and the seat. A new seat concept was proposed to help lessen the loading level to the neck soft tissues. The foam material of the seat back was softened, the initial gap behind the head was reduced and the head restraint was stiffened for firm support. The lower seat back frame was also reinforced to withstand the impact severity at the given delta-V. Another rear impact simulation was conducted using the new seat concept model to examine the effectiveness of the new concept. The joint capsule strain was found to be relatively lower with the new seat concept. The study also discusses the influence of seat parameters to the vertebral motion and the resultant strain in the joint capsules. The meaning of the contact timing of the head to the head restraint was examined based on the results in terms of correlation with injury indicators such as NIC and the joint capsule strain.


Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation.
The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.


Identification of location and timing of guidance cues in sympathetic preganglionic axons of the chick.
The outgrowth of preganglionic axons into the sympathetic trunk of the chick occurs at stages 26-27 (5-5 1/2 d), beginning with C16 and T1 and followed by progressively more caudal spinal cord segments. The direction of preganglionic projections is segment specific, with T1 preganglionic neurons projecting predominantly in the rostral direction and T4 preganglionic neurons projecting predominantly in the caudal direction. These projections are correct from the outset. A previous study (Yip, 1987) has shown that removal of the neural crest, precursors of target ganglion cells, did not alter the trajectories of preganglionic axons, indicating that target cues are not required for the guidance of these axons. The present work extends that study and examines, through surgical manipulations of the developing embryo, the location and time of appearance of preganglionic axonal guidance cues. Spinal cord transplantation experiments show that segment-specific patterns of preganglionic outgrowth are determined by the local environment of axonal growth and not by the identity of preganglionic populations. In addition, spinal cord transplants of age-mismatched donors and hosts indicate that the timing of preganglionic outgrowth is also under local environmental control. These findings suggest that preganglionic axonal outgrowth is guided by local cues which may appear in a controlled spatiotemporal manner.


Thickness mapping of the cornea and epithelium using optical coherence tomography.
To measure corneal and epithelial thickness across four meridians using Optical Coherence Tomography (OCT) and to compare these measurements between normal non-lens wearers (NLW), rigid gas permeable (RGP) lens wearers, and RGP-wearing keratoconics (KC). Both eyes of 60 subjects were measured (20 NLW, nine female:11 male, 27.6 +/- 5.9 years; 20 RGP, 20 female, 23.9 +/- 7.6 years; and 20 KC, seven female:13 male, 32.4 +/- 8.1 years). A customized fixation target employing LEDs in eight directions of gaze was attached to the OCT and corneal images obtained. Raw OCT scans were analyzed to yield values for corneal and epithelial thickness and color-coded maps were compiled. Central corneal thickness (CCT) was thinnest in KC (447 +/- 68 microm) and similar between RGP (518 +/- 32 microm; pKC < 0.001) and NLW (517 +/- 21 microm) (p(KC) < 0.001 NLW pRGP > 0.05). Peripheral corneal thickness in NLW was thickest in the superior temporal and thinnest in the inferior (I) regions (superior temporal(thickest) vs. I(thinnest) p < 0.001). Central epithelial thickness was thinnest in KC (44 +/- 7 microm), followed by RGP (50 +/- 4 microm), then NLW (54 +/- 2 microm) (pKC < 0.001 NLW p(RGP) < 0.05). Central epithelial thickness in the KC group was significantly thinner than in the RGP group (p < 0.001). In the NLW group, peripheral epithelial thickness was thicker (63 +/- 5 microm) than central (p < 0.001) and was thickest in the superior (S) region and thinnest in the inferior (I) region (S(thickest) vs. I(thinnest) p < 0.001). KC epithelium was thinnest in the inferior temporal meridian (42 +/- 5 microm). Thickness of the normal cornea and epithelium was greatest in the superior region. In all groups, the inferior cornea and epithelium was thinnest, and to a greater extent in the KC group.


Wellness in the Face of Frailty Among Older Adults in First Nations Communities.
First Nations people report high levels of wellness despite high rates of chronic illness. Our goal was to understand the factors associated with wellness among First Nations adults in Ontario who were considered frail. Using the First Nations Regional Health Survey, we created a profile of First Nations adults (aged 45+) who were categorized as "frail" (weighted sample size = 8121). We used multivariate logistic regression to determine associations between wellness (as measured by self-reported physical, emotional, mental, and spiritual balance) and determinants of health. Rates of reported wellness were high among those who were frail, ranging from 56.7% reporting physical balance to 71.6% reporting mental balance. Three key elements were associated with wellness: the availability of resources, individual lifestyle factors, and cultural connection and identity. Our findings provide a profile of strength and wellness among older First Nations adults living with frailty.


Can mechanical balloon dissection be applied to cleave fibrotic submucosal tissues? A pilot study in a porcine model.
Removal of a lesion containing an ulcer scar is one of the most challenging applications of endoscopic submucosal dissection (ESD). The present study examined whether a novel balloon dissector could cleave fibrotic submucosal tissue beneath ulcer scars. Six pigs were studied. Endoscopic mucosal resection (EMR) with ligation was performed at 7 or 8 sites in the stomach for each animal; 4 weeks later, 23 sites with a visible scar were selected for submucosal dissection. The procedure involved first creating a submucosal fluid cushion (SFC) by injecting either saline mixed with mesna or pure saline. A slender, compliant balloon with a diameter of 8, 13, or 18 mm was inserted into the SFC. The balloon was unfolded and thrust forward to cleave the fibrotic submucosa over approximately 5 cm. Fibrotic submucosa was dissected within 90 seconds in 17 of 23 attempts. Isolating the ulcer scar from the muscularis with the SFC prior to balloon dissection and using a thinner balloon catheter both ensured a better dissection. The fibrotic submucosa underlying post-EMR scars can be dissected with the novel balloon dissector, although the technique is less effective in cases with no sign of lifting.


Optically trapped mirror for reaching the standard quantum limit.
The preparation of a mechanical oscillator driven by quantum back-action is a fundamental requirement to reach the standard quantum limit (SQL) for force measurement, in optomechanical systems. However, thermal fluctuating force generally dominates a disturbance on the oscillator. In the macroscopic scale, an optical linear cavity including a suspended mirror has been used for the weak force measurement, such as gravitational-wave detectors. This configuration has the advantages of reducing the dissipation of the pendulum (i.e., suspension thermal noise) due to a gravitational dilution by using a thin wire, and of increasing the circulating laser power. However, the use of the thin wire is weak for an optical torsional anti-spring effect in the cavity, due to the low mechanical restoring force of the wire. Thus, there is the trade-off between the stability of the system and the sensitivity. Here, we describe using a triangular optical cavity to overcome this limitation for reaching the SQL. The triangular cavity can provide a sensitive and stable system, because it can optically trap the mirror's motion of the yaw, through an optical positive torsional spring effect. To show this, we demonstrate a measurement of the torsional spring effect caused by radiation pressure forces.


[Small HER2-positive breast cancer: which prognosis and which adjuvant treatment?].
Incidence of centimetric or infracentimetric node negative (pT1a-b, N0) breast cancer is increasing due to screening procedures. Although considered as having an overall favorable prognosis, several retrospective studies have suggested a higher risk of relapse when HER2 is overexpressed. Since randomized studies evaluating trastuzumab in the adjuvant setting did not include T1a-bN0, there is no level I evidence supporting the administration of a trastuzumab-based post-operative chemotherapy in these cases. However, some recent retrospective data suggest a benefit for such a strategy and current guidelines recommend to consider adjuvant chemotherapy plus trastuzumab in pT1bN0. The final decision, as well as the nature of cytotoxics to be administered in combination with trastuzumab, require a careful evaluation of the benefit/risk ratio in order to minimize the risk of toxic events, notably at the cardiac level.


Decreased hydrogen peroxide production and mitochondrial respiration in skeletal muscle but not cardiac muscle of the green-striped burrowing frog, a natural model of muscle disuse.
Suppression of disuse-induced muscle atrophy has been associated with altered mitochondrial reactive oxygen species (ROS) production in mammals. However, despite extended hindlimb immobility, aestivating animals exhibit little skeletal muscle atrophy compared with artificially immobilised mammalian models. Therefore, we studied mitochondrial respiration and ROS (H2O2) production in permeabilised muscle fibres of the green-striped burrowing frog, Cyclorana alboguttata. Mitochondrial respiration within saponin-permeabilised skeletal and cardiac muscle fibres was measured concurrently with ROS production using high-resolution respirometry coupled to custom-made fluorometers. After 4 months of aestivation, C. alboguttata had significantly depressed whole-body metabolism by ~70% relative to control (active) frogs, and mitochondrial respiration in saponin-permeabilised skeletal muscle fibres decreased by almost 50% both in the absence of ADP and during oxidative phosphorylation. Mitochondrial ROS production showed up to an 88% depression in aestivating skeletal muscle when malate, succinate and pyruvate were present at concentrations likely to reflect those in vivo. The percentage ROS released per O2 molecule consumed was also ~94% less at these concentrations, indicating an intrinsic difference in ROS production capacities during aestivation. We also examined mitochondrial respiration and ROS production in permeabilised cardiac muscle fibres and found that aestivating frogs maintained respiratory flux and ROS production at control levels. These results show that aestivating C. alboguttata has the capacity to independently regulate mitochondrial function in skeletal and cardiac muscles. Furthermore, this work indicates that ROS production can be suppressed in the disused skeletal muscle of aestivating frogs, which may in turn protect against potential oxidative damage and preserve skeletal muscle structure during aestivation and following arousal.